While there are a number of analgesic agents currently utilized to relieve mild to severe pain, the search for improved analgesics is a continuing one because of the numerous problems associated with the presently available agents. Aspirin and related salicylates are considered to be non-narcotic analgesic agents useful for relieving mild to moderate pain in addition to their usefulness as anti-inflammatory and anti-pyretic agents. However, the ingestion of salicylic acid or related salicylates may result in epigastric distress, nausea and vomiting. This widely used class of non-narcotic analgesic agents may also cause gastric ulceration and even hemorrhage both in experimental animals and man. Exacerbation of peptic ulcer symptoms and erosive gastritis have all been reported in patients on high dose therapy, i.e., arthritis patients. Aspirin is also one of the most common causes of drug poisoning in young children and has a potential of serious toxicity if used improperly.
Acetaminophen is also considered to be a non-narcotic analgesic agent useful in treating mild pain associated with simple headache, common muscular aches, etc. While acetaminophen is particularly useful for patients who cannot take aspirin, e.g., ulcer patients, its use is contraindicated in individuals who have exhibited a sensitivity to it. In addition to their drawbacks in view of their potential side effects, the mild non-narcotic analgesic agents are not sufficiently potent to relieve the severe pain associated with surgery, cancer and the like. Unfortunately, the potent analgesic agents capable of relieving such severe pain are also narcotic agents and their use entails the risk of producing physical dependence. There are as yet no agents effective against severe pain that are entirely free of this risk.
Thus, there is an urgent need for improved analgesic agents for treating mild as well as severe pain. The present invention provides such agents.
In addition to the need for improved analgesic agents, there is also a need for improved psychotropic agents to provide an alternative to current therapy. The compounds of this invention, in addition to their analgesic activity, also exhibit anti-depressant, tranquilizing, sedative and hypnotic activity. Thus, their usefulness as analgesic agents is enhanced, since many patients suffering from pain also exhibit varying states of anxiety and depression.
A recently identified pentapeptide, methionine enkephalin, has the following structure H-Tyr-Gly-Gly-Phe-Met-OH [see Hughes et al., Nature, 258, 577 (1975)]. This peptide is found in many areas of the brain where it appears to act as a neurotransmitter or neuromodulator in a central pain suppressive system. The natural peptide binds stereo-specifically to partially purified brain opiate receptor sites [for instance, see Bradbury et al., Nature, 260, 793 (1976)], is very active in bioassays for opiate activity, but exhibits only weak analgesic activity of short duration when injected directly into the brain of the rat [for instance, see Belluzzi et al., Nature, 260, 625 (1976)].
In addition, several C-terminal fragments of a 91 chain length peptide known as human, porcine or camel .beta.-lipotropin having the pentapeptide sequence of methionine enkephalin at their N-terminus have been isolated from the pituitary and found to exhibit potent in vitro opioid activity in binding to partially purified brain opiate receptor sites. [see Ling and Guillemin, Proc. Natl. Acad. Sci. USA 73, 3308 (1976) and Proc. Natl. Acad. Sci. USA 73, 1821 (1976)]. The reported fragments have been characterized as .alpha.-endorphin (61-76), .beta.-endorphin (61-91), .gamma.-endorphin (61-77) and .delta.-endorphin (61-87), and .beta.-lipotropin fragments (61-64 61- 68, 61-69, 61-79 and 70-79. Unlike the enkaphalins, the endorphins possesses some pharmacological activity when administered intracerebrally or parenterally. The present invention is directed to novel derivatives of mammalian .alpha.-endorphin which are highly active by a variety of routes of administration and thus are useful as pharmacological and veterinary agents.
We have unexpectedly found that the incorporation of a D-amino acid, such as D-alanine, for the penultimate glycine residue at the N terminus of a .alpha.-endorphin greatly enhances the analgesic activity of these compounds. In addition to their analgesic activity, the compounds also exhibit excellent anti-depressant, sedative, hypnotic, and tranquilizing activity, and additionally have veterinary utility as growth hormone releasing agents and prolactin releasing agents.